The overall goals of this project are to characterize the determinants of vascular structure and function, and evaluate their effects on cardiovascular morbidity and mortality 1. We recently examined the predictive role of pulse wave velocity (PWV), a non-invasive marker of vascular stiffness. In a cross-sectional study involving 504 Baltimore Longitudinal Study of Aging (BLSA) participants who were free of cardiovascular disease at baseline, and with an average follow-up of 6.2 years, we found that PWV was a predictor of cardiovascular events (defined as cardiovascular death, myocardial infarction, revascularization, or stroke) and of total mortality. However, when other factors known to influence cardiovascular morbidity and mortality were entered into the Cox proportional hazards model, PWV was no longer an independent predictor of outcomes, suggesting that increased stiffness may represent a mechanism through which the significant variables (namely age, fasting blood sugar, and white blood cells) exert their deleterious effects on cardiovascular morbidity and mortality 2. In order to investigate the hypothesis that the age-associated changes in cardiovascular structure and function represent the mechanism through which increased age exerts its deleterious effects on cardiovascular morbidity and mortality, and to test the related hypothesis that physiologic vascular properties explain the chronologic age-associated increased risk of atherosclerosis, we plan to evaluate traditional as well as novel measures of vascular properties, and examine how they relate to non-invasive assessments of atherosclerosis. This will be performed in 300 BLSA subjects as well as individuals with known absence of coronary artery disease and patients with known premature coronary artery disease. A research and development contract has been awarded to procure novel non-invasive imaging tools such as electron beam computed tomography, vascular magnetic resonance imaging, and vascular magnetic resonance angiography (Project Officer, S. Najjar). 3. Although it is thought that the relationship between central and peripheral pulse pressure changes with advancing age, this has not been systematically investigated in a large cohort. This is important because peripheral pulse pressure, a surrogate measure of vascular stiffness, has recently been shown in numerous studies to be an independent predictor of adverse outcomes. If the difference between peripheral and central pulse pressure decreases with age, this would suggest that peripheral pulse pressure underestimates the risk of adverse outcomes in older individuals. We are therefore determining the central aortic pressures in a large cohort of BLSA individuals across a broad age-range, by analyzing carotid arterial pulse wave contours obtained non-invasively by the technique of applanation tonometry with high fidelity micromanometer probes. 4. Previous studies from the Laboratory of Cardiovascular Science had previously shown that a novel nonenzymatic breaker of advanced glycation end-products, ALT-711, improves vascular stiffness and lowers pulse pressure in humans with increased vascular stiffness, and that it improves both arterial and ventricular function and optimizes ventriculo-vascular coupling in old healthy monkeys. We are presently participating in a multi-center, phase II, randomized, double-blinded, placebo-controlled study that evaluates, in a formal dose-finding study, the safety and efficacy of ALT-711 in reducing blood pressure in subjects with isolated systolic hypertension, which is the most common form of hypertension that afflicts older individuals. 5. Congestive heart failure is a clinical syndrome whose prevalence and incidence are increasing, especially in older individuals. We hypothesize that increased vascular stiffness, by accentuating the ventriculo-vacular mismatch, adversely affects the already compromised cardiovascular performance. L-arginine, but not its enantiomer D-arginine, is the substrate for nitric oxide synthase, the enzyme that catalyzes the synthesis of nitric oxide, which, in turn, decreases vascular stiffness, hastens ventricular diastolic relaxation and enhances diastolic distensibility. We are therefore investigating, in a randomized double-blinded cross-over study, the acute vascular and diastolic ventricular effects of parenteral L-arginine and D-arginine administration in patients with heart failure and increased vascular stiffness, and evaluating whether these effects favorably impact cardiovascular performance.